Infection remains the most frequent illness of man and one of the most common causes of death. The investigations proposed here seek to gain understanding of the physiology of host defense against infection, especially bacterial and fungal infection. More effective prevention and management of infections in the normal or compromised host and the eventual manipulation of the immune system to enhance its protective effects are the ultimate goals. Mechanisms involved in the interaction of bacteria and fungi with phagocytes and with complement will be studied in the following specific projects: (1) Studies of the mechanisms of bacterial and fungal killing by mononuclear phagocytes and of the biochemical changes that permit enhanced killing by activated macrophages. Respiratory burst oxidase activities in subcellular fractions and plasma membrane lipid composition will be compared for normal and activated macrophages, and oxidative metabolism and interaction with herpes simplex virus will be compared in monocytes from adults and newborn infants. The effect of the adjuvant muramyl dipeptide on macrophage function will be studied after administration in vivo and after incubation with newborn and adult monocytes in vitro. "Activation" of monocytes by neutrophil proteases will be examined, as will the effects on oxidative metabolism of binding and ingestion by normal and activated macrophages through Fc receptors, C3b receptors, or both. (2) Studies of the generation of microbicidal oxygen metabolites by human neutrophils. The enzyme responsible for the respiratory burst, and possible amplification of that respiratory burst by lysosomal lactoferrin will be analyzed, as will "activation" of neutrophils by endotoxin and muramyl dipeptide. Metabolic inhibitors will be used to investigate the biochemical basis of this activation. (3) Studies of the role of the alternative complement pathway in resistance to bacterial infection. The relationship between this mechanism and infections will be studied in individuals with malnutrition and sickle cell disease.